Mutant presenilin 2 transgenic mice - A large increase in the levels of A beta 42 id presumably associated with the low density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin

The N141I mutation in presenilin (PS) 2 is tightly linked with a form of au tosomal dominant familial Alzheimer's disease in the Volga German families. We previously reported that mouse brains harboring mutant PS2 contained in creased levels of amyloid beta protein (A beta) 42 in the Tris-saline-solub le fraction (Oyama, F., Sawamura, N., Kobayashi, K., Morishima-Kawashima, M ., Kuramochi, T., Ito, M., Tomita, T., Maruyama, K., Saido, T. C., Iwatsubo , T., Capell, A., Waiter, J., Grunberg, J., Ueyama, Y., Haass, C. and Ihara , Y. (1998) J. Neurochem. 71, 313-322). Here, using a new extraction protoc ol, we quantitated the A beta 40 and A beta 42 levels in the Tris-saline-in soluble fraction. The insoluble A beta levels were found to be higher than the soluble A beta levels, and the insoluble A beta 42 levels were markedly increased in mutant PS2 transgenic mice. To investigate the origin of the insoluble A beta 42, we prepared the detergent-insoluble, low density membr ane fraction. This fraction from two independent lines of mutant PS2 transg enic mice contained remarkably increased levels of A beta 42 and significan tly low levels of glycerophospholipids and sphingomyelin. This unexpected f inding suggests that a large increase in the levels of A beta 42 in mutant PS2 mice is presumably induced through alterations of the lipid composition in the low density membrane domain in the brain.